Science Friday - A Nobel Prize For Chemistry Work ‘Totally Separate From Biology’

Episode Date: December 2, 2024

In 2022, the Nobel Prize in Chemistry went to Dr. Carolyn Bertozzi of Stanford University, Dr. Morten Meldal of the University of Copenhagen, and Dr. K. Barry Sharpless of the Scripps Research Institute “for the development of click chemistry and bioorthogonal chemistry.” In “click chemistry,” molecular building blocks snap together quickly and efficiently to let chemists build more complicated molecules. But bioorthogonal chemistry takes that work one step further, allowing the technique to be used within living organisms without damaging cells.“When someone is thinking outside the box, or in a very different way, we like to think of that as orthogonal thinking,” Bertozzi explained. “So biorthogonal means not interacting with biology. Totally separate from biology.” Her research began with an interest in developing ways to see specific sugar molecules on the surface of cells. But it has developed into an approach that can be used for advanced drug delivery in fields such as chemotherapy.As part of Science Friday’s 33rd anniversary show, we’re revisiting our listeners’ favorite stories, including this one. In 2022, Bertozzi joined Ira Flatow for a wide-ranging conversation about her research, chemistry education, her early music career, and the importance of diversity in the field of chemistry.Transcripts for each segment will be available after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Research that won a Nobel Prize a couple years back could specifically target cancerous tumors much better than traditional chemotherapy can. So you get this burst of toxic drug only in the tumor and nowhere else in the body, and it kills the tumor without these toxic side effects. It's Monday, December 2nd, and you're listening to Science Friday. I'm SciFri producer Deep Peter Schmidt.

We're continuing to celebrate our 33rd anniversary with some of our listeners' favorite segments. And you know what? High on that list was this 2022, conversation with Nobel Prize-winning chemist, Dr. Carolyn Bertotzi. Here's her conversation with Araflato. Today, bio-orthogonal chemistry is a staple in biological research and a promising tool for medicine. These reactions involve two chemicals that can bond with each other, even in an environment as complicated as the human body. And they don't interfere with the normal chemical reactions in the body.

Its pioneer won the Nobel Prize in chemistry for her research. Let me bring her on now. Dr. Carolyn Britozzi, 2022 Nobel Prize laureate and Professor of Chemistry at Stanford in Palo Alto, California. Congratulations and welcome to Science Friday. Thank you so much. It's really wonderful to be here. Nice to have you. Okay, let's start with the basics. What does it mean for chemistry to be bio-orthogonal? Pretty big word there. Yes, it's a bit of a mouthful, but you can break it down into its two parts. So the word orthogonal is one that we usually use when we're trying to describe two things that don't interact with each other. When someone is really thinking outside the box or in a very different way, we like to think of that as orthogonal thinking. So bio-orthogonal means not interacting

with biology, totally separate from biology. And we invented that concept because we had ideas for how such a chemistry could be useful in biology and medicine. Give me your idea of how useful it is. Well, it started with a very specific application in mind. And what the backstory is, is that I had a longstanding interest in the biology of complex carbohydrates. And people might think of that term as having to do with food that you eat, but there's a whole different world of biology of complex carbohydrates, which is that they're basically like a forest

that decorates the entire surface of every cell in your body. And we wanted to be able to study those complex carbohydrates, and we wanted to image them. We wanted to be able to see them in microscopes or see them in a magnetic resonance imaging scan or a pet scan. And there was no way to see them. So the very early genesis of bioorthogonal chemistry was as a tool to be able to study and to visualize those cell surface sugar molecules. And why do you want to know so much about how the sugar molecules are working on the cell surface? Well, even back in the 1990s, which is when I started this whole area of research, people knew that the structures of cell surface sugars change. during diseases. And the area in which this had been studied most extensively was in cancer. So people knew that if you looked at the surface of cancer cells, the sugars had changed

compared to the normal cells around them. And anytime there's a change in molecules between healthy tissue and cancerous tissue, you might be able to exploit that as a means to visualize those disease cells and to detect the disease. But the problem was, at that time, the only way to study those sugars was on cells and tissues that you took out of the body and ground up into bits and pieces and destroyed. And there was really no way to look at the sugars on the cells when they were alive and in the body.

And that's what you need to do if you want to be able to detect these changes for cancer detection or cancer diagnosis. And so how does looking at sugars connect to the idea of this orthogonal model? How did you apply it? Well, you know, it's funny because science usually has a backstory of accidents and serendipity. And this story has an element of that. So way back when I was a postdoctoral fellow, and so this is before I was a professor. Instead, I was a researcher in someone else's lab at the time. And I was thinking about the sugars and frustrated that there was no. way to visualize them. And other molecules like proteins and DNA and RNA, other stuff that you

find in cells and animals and humans, there were actually some really nice technologies to look at those other molecules, but there was just a gap. There was nothing for the sugars. And then I happened to go to a conference in Southampton, England, of all places, as a postdoctoral fellow, and I heard a lecture from a German biochemist named Werner Reuter. And in that lecture, he talked about the fact that you could feed cells chemically altered versions of very simple sugars. And as long as the alterations were very subtle, not too dramatic, those altered sugars would get metabolized by the cells and they would be incorporated into the cell surface complex carbohydrates. So you could actually make the cells turn into what they eat. You've heard the phrase, you are what you eat, right?

And these cells actually were putting altered sugars on the surface just because they were eating the little simple precursors. And so that gave me an idea for how you could sneak a little bit of chemistry into cell surface sugars and then use the chemistry to attach probe molecules for imaging. And it was a very simple idea at the time, but there was a huge problem with the idea because you would need the simple chemistry to be what we later termed bio-orthogonal. And there really wasn't a chemistry that existed at that time that would allow you to do such a thing. So that was where the motivation came from. And if I hadn't seen that lecture by Professor Reuter, I'm not sure I would have had this idea anytime soon. Well, how do you guarantee that your bio-orthogonal chemistry

is only going to react with the one specific thing you wanted to? Well, that is the central challenge in the whole area is to find these, you know, magical chemistries that even though there's thousands of other chemicals in your body, that somehow they're willing to ignore all of that and yet still react with something else that's biorethogonal. And we spent many years engineering the chemical groups so that they would have exactly this sort of thread the needle capability. and you have to do a lot of experimentation. So when we made new functional groups, which is what we call chemical groups, well, we would test them. We would test them in cells in a dish, first and foremost. And we would do a lot of experiments to see whether they were attaching themselves

unwittingly to some of the biological molecules. And if they did, we threw them in the garbage can and went back and try a different type of chemical. And once we got them to be very clean in cells, then we would test them in animals. And enough of that has now transpired over the last 25 years that we now are very confident that we have a toolkit of bio-orthogonal chemistries that are so safe that some of them are now being tested in human clinical trials. They're inside the body of human patients.

Well, that brings me to the meat of my next question, so to speak. Give me some ideas of how you might apply this chemistry. Well, right now, the two leading, applications have to do with drug delivery, right? So especially for cancer. And we all know that the types of medicines people are traditionally treated with for cancer, which we call chemotherapies, they can be really toxic and hard to handle. And the way that those medicines work is they kill cancer cells, but they also kill some of your healthy cells at the same time. And that's why people on chemo have these side effects, like losing their hair and being very nauseated, and sometimes having

organ damage. And on a bad day, the drug might do more harm than good to a cancer patient. So one of the challenges is to figure out how do you send that toxic drug to the cancer cell specifically, like a guided missile and keep it away from all the other cells in the body? And bioorthogonal chemistry has turned out to be useful for this. And so as a case in point, there is a biotech company here in the Bay Area outside San Francisco that I am an advisor for. And they have a protocol to treat patients with soft tissue sarcoma. That's a particular type of cancer in bones. And the way they do this is they inject into the tumor area a material.

It's a hydrogeal polymer and it's actually quite similar to the same material that's, injected cosmetically for people who want filler. If you've ever heard of cosmetic fillers, there's literally a polymer that gets injected into the face where a person wants to fill a wrinkle, for example. Yeah, we're not talking Botox here, right? No, not Botox. This is a different substance. It's harmless. It just kind of puffs up your skin. Okay. So what this company has done is they have modified that same material with a bio-orthogonal chemical. And they inject that material into the tumor. does nothing but fill up space, it's harmless. That bioorthogonal chemical has no interaction with the human body, just sitting there. But then, the next day, they inject the chemotherapy

drug systemically. They put it, you know, in the typical way in an IV bag. So the patient sits there and they have an IV infusion of chemotherapy. But the chemotherapy is rendered harmless by attachment of another bioorthogonal chemical. And it floats through it. the body, throughout circulation, doing nothing is totally harmless. But when it encounters that material that was injected on the previous day, the two biorethogonal chemicals see each other and they react. And that reaction releases the active chemotherapy right there locally in the environment of the tumor. So you get this burst of toxic drug only in the tumor and nowhere else in the body and it kills the tumor without these toxic side.

effects. And they are now performing this procedure on patients in what's called a phase one clinical trial. So they're looking to make sure that it's safe and to figure out what are the right doses of the two components. And if everything goes well, they'll start a next phase where they look for reduction of the tumor burden and benefit to the patient. After the break, how this approach to targeting tumors could be used to help treat other diseases. Hi there, Ira here, letting you know that we have a dollar-for-dollar match right now, so any donation you make will be doubled. And this week, we're celebrating Giving Tuesday, which means now is a great time to double your impact and show your support for Science Friday, a nonprofit dedicated to making science accessible to the public.

So please go to science friday.com slash support to make your donation and invest in the future of science journalism. Again, that's science friday.com slash support and thanks. Are there other drug applications or other diseases, tumors, you name it, that this might work with? Yes, there's another group in New York that is gearing up for a clinical trial to target radioisotopes to cancers. And these are like nuclear particles that release radiation that's damaging to the tumor. Also, it's a way of basically delivering the radiation very specifically to the tumor and keeping the damage away from other tissues. And it's kind of a similar strategy. They put one molecule in first, and it's actually an antibody that's armed with a biorethogonal

chemical. And that antibody is like a heat-seeking missile, which goes to the tumor and latches onto it. And then in a second step, they add the radioactive particle, which has the other biorethogonal partner on it. And it will then find that antibody and do the reaction. And now that radioactive particle is also concentrated in the tumor. So it's kind of a similar approach, but instead of a chemotherapy drug, it's a radioactive particle. And instead of a polymer that gets injected, it's an antibody that finds its way. But I think that theme is one that you'll find being tested again and again and again, and it's something you really couldn't even conceive of doing without the availability of

bio-orthogonal chemistries. I've heard the work your connobleist did called click chemistry. Is this kind of a click chemistry you're talking about? Yes, you know, there are many overlapping concepts between bio-orthogonal and click chemistry. And that's why I think the Nobel Foundation kind of put us together into this one prize. The click chemistry term was coined by Barry Sharpless. And he shares the prize with myself and another chemist named Morton Meldall. Barry was interested in reactions that have the property that they're very reliable.

They form products in very high yield. And they do so without interference by other functional groups on the same. molecules. So you can see how that's a similar, you know, challenge to our own thinking about bio-orthogonal chemistry. The big difference is that when Barry was conceiving of click chemistries, he was thinking about them as tools for the synthesis of complex molecules, which is another big challenge in the chemical sciences. And Morton Meldall had a similar motivation. You know, both he and Barry are synthetic chemists. They like to make big, complicated molecules, and having these click chemistries can get you to those big complicated molecules

much more easily. You know, people say chemistry is so boring, right? People are wrong. Well, this is a great example of that. What sort of advice would you give people coming to you, you know, for future scientists? I'm sure you would point them in your direction, because as we say, Chemistry is a lot less boring than you think it is. That's correct. I think the misconception of chemistry being boring might be our own fault because I think chemists teach students and usually the first exposure is somewhere in high school. I think we teach those high school students in a kind of boring way.

You think? I think so. And I say that as someone who took chemistry in high school, I can tell you that's the truth. It was true for me too, I hate to say. I took chemistry in high school, and I don't know that I hated it, but I didn't like it. Yeah. It was boring. It was boring.

And it didn't seem relevant to me or the world at all. And then I went to college, and I was, at first, I was a pre-med. And so you have to take some chemistry classes if you're destined for medical school. So I did, not because I wanted to, but because I had to. and even in freshman chemistry, I was not interested. Again, it didn't seem all that relevant or interesting to me. So, you know, I'm just like you in that regard. And if I had not taken organic chemistry,

I think I probably wouldn't have discovered the field as an exciting field. But organic chemistry turned things around for me. And that's when I realized that chemistry is so central in biology and biomedicine. And if you want to understand disease, you know, human disease and figure out how to treat diseases, you really need to be a chemist. So I'm really glad that I stuck with it long enough to discover organic chemistry because that sealed it for me. But I think if we did a better job teaching in the early stages, people wouldn't have this bias against chemistry. It's fascinating.

And there's so much we don't know and so many discoveries yet to be made. The field I think of is still very young. So now you have this huge stage as a Nobel winner. You're in the spotlight. Are there things you want to use that power? or visibility to try to do that maybe you couldn't just as a chemist? This is a really interesting question. You know, I certainly have philosophies that I would like people to think about

and maybe even embrace having to do with the diversity of scientists needing some enhancement in order for us to do the best science we can do, especially in the physical sciences like chemistry. there are many different, you know, underrepresented groups who have been historically excluded from the field and whose talent we haven't been able to avail ourselves of, which limits progress. Hopefully now people will pay attention to the importance of diversifying the chemical workforce so that we can take advantage of all the talent. That's one thing I would like to convey. And, you know, the interesting thing is lots of chemists, including myself, have been advocating. for greater diversity among our ranks.

But if you are awarded a Nobel Prize and your strategy for success has been to have the most diverse lab that you can have, I think that that gives, you know, some validation to the idea that diversity breeds success. Dr. Carolyn Bertotsi is Professor of Chemistry at Stanford University in Palo Alto and 2022 winner of the Nobel Prize. Thank you so much for having me. And that's all the time we have for today. Lots of folks help make the show happen, including

Sandy Roberts, Beth Rami, John Dancosky, Emma Gomez. On tomorrow's episode, we'll do some time travel and figure out what it would have been like to witness the end of the dinosaurs. I'm SciFry producer Deep Petersmith. Thanks for listening.